Dataset Information

Interferon ? and Anti-PD-1/PD-L1 Checkpoint Blockade Cooperate in NK Cell-Mediated Killing of Nasopharyngeal Carcinoma Cells.

ABSTRACT: Nasopharyngeal carcinoma (NPC) is a highly malignant epithelial cancer linked to EBV infection. Addition of interferon-? (IFN?) to chemo- and radiochemotherapy has led to survival rates >90% in children and adolescents. As NPC cells are sensitive to apoptosis via tumor necrosis factor-related apoptosis inducing ligand (TRAIL), we explored the role of TRAIL and IFN? in the killing of NPC cells by natural killer (NK) cells. NPC cells, including cells of a patient-derived xenograft were exposed to NK cells in the presence or absence of IFN?. NK cells killed NPC- but not nasoepithelial cells and killing was predominately mediated via TRAIL. Incubation of NK cells with IFN? increased cytotoxicity against NPC cells. Concomitant incubation of NK- and NPC cells with IFN? before coculture reduced cytotoxicity and could be overcome by blocking the PD-1/PD-L1 axis leading to the release of intracellular TRAIL from NK cells. In conclusion, combination of IFN? and anti-PD-1, augmenting cytotoxicity of NK cells against NPC cells, could be a strategy to improve NPC-directed therapy and warrants further evaluation in vivo.

SUBMITTER: Makowska A

PROVIDER: S-EPMC6617170 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Interferon β and Anti-PD-1/PD-L1 Checkpoint Blockade Cooperate in NK Cell-Mediated Killing of Nasopharyngeal Carcinoma Cells.

Makowska Anna A Braunschweig Till T Denecke Bernd B Shen Lian L Baloche Valentin V Busson Pierre P Kontny Udo U

Translational oncology 20190708 9

Nasopharyngeal carcinoma (NPC) is a highly malignant epithelial cancer linked to EBV infection. Addition of interferon-β (IFNβ) to chemo- and radiochemotherapy has led to survival rates >90% in children and adolescents. As NPC cells are sensitive to apoptosis via tumor necrosis factor-related apoptosis inducing ligand (TRAIL), we explored the role of TRAIL and IFNβ in the killing of NPC cells by natural killer (NK) cells. NPC cells, including cells of a patient-derived xenograft were exposed to ...[more]

PMID: 31295651

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Project description:Blocking the interaction between the programmed cell death (PD)-1 protein and one of its ligands, PD-L1, has been reported to have impressive antitumor responses. Therapeutics targeting this pathway are currently in clinical trials. Pembrolizumab and nivolumab are the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ipilimumab-refractory melanoma. Nivolumab has been associated with improved overall survival compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma. Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune- checkpoint inhibitors for use in other cancers: nivolumab, an anti-PD-1 monoclonal antibody, for Hodgkin lymphoma, and MPDL-3280A, an anti-PD-L1 monoclonal antibody, for bladder cancer and non-small cell lung cancer. Here we review the literature on PD-1 and PD-L1 blockade and focus on the reported clinical studies that have included patients with melanoma.PubMed was searched to identify relevant clinical studies of PD-1/PD-L1-targeted therapies in melanoma. A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic.The anti-PD-1 and anti-PD-L1 agents have been reported to have impressive antitumor effects in several malignancies, including melanoma. The greatest clinical activity in unselected patients has been seen in melanoma. Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade. However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade. Combination checkpoint blockade with PD-1 plus cytotoxic T-lymphocyte antigen (CTLA)-4 blockade appears to improve response rates in patients who are less likely to respond to single-checkpoint blockade. Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (eg, interleukin 2, CTLA-4 blockade). Certain adverse events can be severe and potentially life threatening, but most can be prevented or reversed with close monitoring and appropriate management.This family of immune-checkpoint inhibitors benefits not only patients with metastatic melanoma but also those with historically less responsive tumor types. Although a subset of patients responds to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates. Combination therapies appear to be a means of increasing response rates, albeit with increased immune-related adverse events. As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.

Dataset Information

Interferon ? and Anti-PD-1/PD-L1 Checkpoint Blockade Cooperate in NK Cell-Mediated Killing of Nasopharyngeal Carcinoma Cells.

Publications

Interferon β and Anti-PD-1/PD-L1 Checkpoint Blockade Cooperate in NK Cell-Mediated Killing of Nasopharyngeal Carcinoma Cells.

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